4-(4-Phenyl-1-piperidinyl)methyl-5-acyl-1,3-dihydro-2H-imidazol-2-ones

ABSTRACT

1,3-Dihydro-2H-imidazol-2-ones having 5-acyl and 4-(4-phenyl-1-piperidinyl)methyl substituents, are useful as cardiotonics, antihypertensives and antithrombotic agents. The compounds are obtained by the reaction of an appropriate substituted piperidine with a substituted 4-bromomethyl-1,3-dihydro-2H-imidazol-2-one.

The present invention relates to imidazoles that have an acyl and a(4-phenyl-1-piperidinyl)methyl substituent at the 4- and 5-positions.More particularly, it relates to compounds having the following generalformula: ##STR1## wherein R is hydrogen, lower alkyl of 1-4 C, loweralkanoyl of 2-4 C, or benzoyl; R¹ is lower alkyl of 1-4 C, phenyl,halophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl,dimethylaminophenyl, dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furyl,2-thienyl or pyridyl; R² is hydrogen or lower alkyl of 1-4 C; X ishydrogen halogen, methyl, methoxy or trifluoromethyl; Y is hydrogen,hydroxy, cyano, acetyl or (C₁₋₄ lower alkoxy)carbonyl; Y¹ is hydrogen orY and Y¹ together form a double bond. The present invention furtherencompasses the pharmaceutically acceptable acid addition salts of theabove compounds.

The lower alkyl groups referred to above contain 1 to 4 carbon atoms.Examples of such lower alkyl groups are methyl, ethyl, propyl, isopropyland butyl. Examples of lower alkoxy groups are methoxy, ethoxy andpropoxy. The lower alkanoyl groups referred to above contain 2 to 4carbon atoms and can be exemplified by acetyl, propionyl and butyryl.Examples of the halogens referred to above are fluorine, chlorine, andbromine. Examples of the halophenyl groups are fluorophenyl,chlorophenyl and bromophenyl.

Illustrative of the pharmaceutically acceptable acid addition salts ofthe compounds of the present invention are salts with inorganic acidssuch as, for example, hydrochloric, hydrobromic, sulfuric, phosphoricand like acids; with organic carboxylic acids such as, for example,acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic anddihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranilic, cinnamic, salicyclic, 4-aminosalicyclic,2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids; and withorganic sulfonic acids such as methanesulfonic acid andp-toluenesulfonic acid.

Where R is hydrogen in the compounds of the present invention, severaltautomeric forms of the compounds are possible as follows: ##STR2##wherein --NR³ R⁴ is substituted 1-piperidinyl as described above and thevarious groups are as defined earlier. These tautomers are acidic andcan react with strong bases to form pharmaceutically acceptable salts ofthe following formulas: ##STR3## wherein the various groups are definedas above and M is a pharmaceutically acceptable alkali metal such assodium or potassium. Throughout this disclosure, the term imidazol-2-oneshall be taken to mean any of the tautomers or the tautomer salts as setforth above.

As examples of compounds of the present invention are the following:

4-Benzoyl-5-[[4-(4-chlorophenyl)-1-piperidinyl]methyl]-1,3-dihyro-2H-imidazol-2-one.

4-Propionyl-5-[[4-(2-methylphenyl)-1-piperidinyl]methyl]-1,3-dihydro-2H-imidazol-2-one.

5-[[4-(4-Fluorophenyl)-1-piperidinyl]methyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

5-[[4-(2-Bromophenyl)-1-piperidinyl]methyl]-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

4-(3-Pyridylcarbonyl)-5-[[4-(2-methylphenyl)-1-piperidinyl]methyl]-1,3-dihydro-2H-imidazol-2-one.

4-[(4-Phenyl-4-methoxycarbonyl-1-piperidinyl)methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-one.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-[1-[4-(2-methylphenyl)-1-piperidinyl]ethyl]-2H-imidazol-2-one.

1,3-Dihydro-5-(4-methoxybenzoyl)-4-[(4-phenyl-1,2,3,6-tetrahydro-1-pyridinyl)methyl]-2H-imidazol-2-one.

5-(4-Methoxybenzoyl)-4-[(4-hydroxy-4-phenyl-1-piperidinyl)methyl]-1,3-dihydro-2H-imidazol-2-one.

1,3-Dipropionyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-[[4-(4-chlorophenyl)-1-piperidinyl]methyl]-2H-imidazol-2-one.

1,3-Dibenzoyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-[[4-(4-chlorophenyl)-1-piperidinyl]methyl]-2H-imidazol-2-one.

1,3-Dihydro-1,3-diethyl-4-(4-methoxybenzoyl)-5-[[4-(4-chlorophenyl)-1-piperidinyl]methyl]-2H-imidazol-2-one.

The compounds of the present invention are prepared by the brominationof a 1,3-diacetyl imidazolone such as a compound of the formula ##STR4##wherein Z is hydrogen to give the compound wherein Z is Br. The reactionis carried out using N-bromosuccinimide in the presence of a freeradical initiator such as benzoyl peroxide in an appropriate solventsuch as carbon tetrachloride. The specific diacetyl starting materialsare obtained from the corresponding 1,3-unsubstituted imidazolone byacetylation with acetyl chloride or acetic anhydride and theunsubstituted imidazolones used are prepared in Belgian Pat. No. 883,856or they can be prepared by the same general procedures described in thepatent.

The bromo compounds obtained above can be treated with hydrobromic acidin acetic acid to remove one or both of the N-acetyl groups. Theresulting imidazolone is then treated with the appropriate amine of theformula ##STR5## wherein X, Y and Y¹ are defined as above, to give thedesired compounds of the present invention.

Although the present process has been described using 1,3-unsubstitutedimidazolones, it is also possible to use the corresponding 1,3-diacetylcompounds or similarly substituted compounds but, when such compoundsare used, the amine will also react with the acyl group to give thedeacetylated imidazolone and an N-acyl amine. It is thus necessary touse an excess of the amine to allow for this reaction but this would notbe a desirable process when the amine used is not readily available andinexpensive.

The compounds in which R represents lower alkanoyl or benzoyl areobtained by reaction of the compounds in which R represents hydrogenwith an excess of the appropriate acid anhydride or acid chloride.

The compounds of the present invention can be used in the treatment ofcardiac failure including congestive heart failure, backward heartfailure, forward heart failure, left ventricular heart failure, or rightventricular heart failure or in the treatment of any other conditionwhich requires the strengthening of heart action with a cardiotonic. Inmany respects, these compounds possess digitalis-like action. Thecompounds of the present invention can also be used in the treatment ofhypertension including primary or essential hypertension, hormonallyinduced hypertension, renal hypertension and chemically inducedhypertension. Finally, the compounds of the present invention can alsobe used as anti-thrombotics. They affect the coagulation of blood bypreventing the aggregation of blood platelets, which play a dominantrole in thrombotic conditions both in the initial event and at theocculsive stage. Arterial thrombosis, particularly in arteries supplyingthe heart muscle and brain, is a leading cause of death and disability.

Antihypertensive activity for the present compounds was demonstratedusing groups of 12 spontaneously hypertensive rats. Blood pressure wasmeasured by a pressure cuff occluder around the base of the tails of therats. The blood pressure was determined in the animals, test compoundwas administered orally in a vehicle at a dose of 50 mg/kg and bloodpressure was measured again at 1, 2, 3, 4 and 24 hours afteradministration of the test compound. The difference in blood pressureobserved was analyzed to establish if it was statistically significant.The vehicle used in administering the test compound did not have asignificant effect on blood pressure when used alone.

Cardiotonic activity for the present compounds was demonstrated by thefollowing procedure. A Walton-Brodie strain gage arch was surgicallyimplanted on the heart of anesthetized dogs to measure cardiaccontractile force. After the vital signs of the animal were stable for10 minutes, test compound was administered intravenously starting at adose of 0.3 mg/kg and continuing with higher doses of 1, 3 and 10 mg/kgif no effect is observed. Active compounds, such as compounds of thepresent invention, which increase cardiac contractile force measured inthis way exert a true positive inotropic effect, or a cardiotoniceffect.

Antithrombotic activity for the present compounds is demonstrated by thefollowing procedure. When adenosine diphosphate is added to citratedplatelet rich human plasma, a typical aggregation of blood plateletsoccurs. Antithrombotic activity is determined by adding a test compoundto the citrated platelet rich human plasma in concentrations of 3, 10,30 and 100 μg/ml and subsequently adding adenosine diphosphate andobserving the extent of inhibition of aggregation of blood platelets.

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formof pharmaceutical preparations to the patient being treated eitherorally or parenterally, that is, intravenously or intramuscularly. Theamount of compound administered will vary with the severity of thehypertension, cardiac failure or blood clotting and the mode ofadministration. For oral administration the antihypertensively effectiveamount of compound is from about 0.1 mg/kg (milligrams per kilograms) ofpatient body weight per day to about 100 mg/kg of patient body weightper day and preferably from about 5 mg/kg of patient body weight per dayto about 30 mg/kg of patient body weight per day.

For parenteral administration the antihypertensively effective amount ofcompound is from about 0.01 mg/kg of patient body weight per day up toabout 50 mg/kg of patient body weight per day and preferably from about0.1 mg/kg of patient body weight per day up to about 20.0 mg/kg ofpatient body weight per day. For oral or parenteral administration thecardiotonically effective amount of compound is from about 0.1 mg/kg ofpatient body weight per day up to about 50 mg/kg of patient body weightper day and preferably from about 0.1 mg/kg of patient body weight perday up to about 20.0 mg/kg of patient body weight per day. For oral orparenteral administration the anticoagulant effective amount of compoundis from about 0.1 mg/kg of patient body weight per day up to about 100mg/kg of patient body weight per day and preferably from about 0.1 mg/kgof patient body weight per day up to about 50 mg/kg of patient bodyweight per day.

For oral administration a unit dosage may contain, for example, from 10to 100 mg of the active ingredient. For parenteral administration a unitdosage may contain, for example, from 5 to 50 mg of the activeingredient. Repetitive daily administration of the compounds may bedesired and will vary with the condition of the patient and the mode ofadministration.

As used herein the term patient is taken to mean a warm blooded animal,for example, birds, such as chickens and turkeys, and mammals, such asprimates, humans, sheep, horses, bovine cows and bulls, pigs, dogs,cats, rats and mice.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose andcornstarch. In another embodiment the compounds of the invention can betableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable doses of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils which can be employed in thesepreparations are those of petroleum, animal, vegetable or syntheticorigin, for example, peanut oil, soybean oil and mineral oil. Ingeneral, water, saline, aqueous dextrose and related sugar solutions,ethanol and glycols such as propylene glycol or polyethylene glycol canbe used as liquid carriers for injectable solutions. Particularlypreferred are combinations of the above carriers such as aqueous ethanolor propylene glycol-aqueous ethanol at alkaline pH.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubbermanufactured by the Dow-Corning Corporation.

Following are illustrative pharmaceutical formulations which may beemployed in practicing the present invention:

PREPARATION OF A TABLET FORMULATION

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        (a)  1,3-Dihydro-4-(4-methoxybenzoyl)-5-                                                                   100     mg                                            [ (4-phenyl-1-piperidinyl)methyl]-                                            2H-imidazol-2-one hydrochloride                                          (b)  Cornstarch              15      mg                                       (c)  Lactose                 33.5    mg                                       (d)  Magnesium stearate      1.5     mg                                       ______________________________________                                    

PREPARATION OF A PARENTERAL FORMULATION

    ______________________________________                                        (a)  1,3-Dihydro-4-(4-methoxybenzoyl)-                                                                     0.100    g                                            5-[4-phenyl-1-piperidinyl)methyl]-                                            2H-imidazol-2-one                                                        (b)  Sodium hydroxide        0.025    g                                       (c)  Ethanol                 1.516    g                                       (d)  Propylene glycol        8.264    g                                       (e)  Water for injection qs ad                                                                             20.0     ml                                      ______________________________________                                    

The following examples are set forth to illustrate the preparation ofcompounds employed in the present invention but should not be construedas limiting it in any way.

EXAMPLE 1

To a stirred mixture of 98.1 g (1 mole) of1,3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 moles) of anhydrousaluminum chloride and 500 ml of nitrobenzene there is added dropwiseover 10 minutes, 158.6 g (1 mole) of p-fluorobenzoyl chloride. Themixture is stirred at 60°-65° C. for 6 hours, then poured onto 2 kg ofice. The precipitate which forms is separated by filtration, washed withdiethyl ether and water and recrystallized from dimethylformamide togive 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one meltingat about 289°-292° C.

If the above procedure is repeated using1,3-dihydro-4-methyl-2H-imidazol-2-one and the appropriate acidchloride, the following compounds are obtained:

1,3-Dihydro-4-methyl-5-[4-(methylsulfonyl)benzoyl]-2H-imidazol-2-one.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one melting atabout 257°-258° C. (dec.) after recrystallization fromisopropanol-water.

4-Benzoyl-1,3-dihydro-5-methylimidazol-2-one melting at about 250°-254°C.

1,3-Dihydro-4-methyl-5-(2-thiophenecarbonyl)-2H-imidazol-2-one meltingat about 212°-215° C. In this case, the material obtained after pouringthe mixture onto ice water is extracted into ethyl acetate and the ethylacetate solution is dried and the solvent is evaporated.

1,3-Dihydro-4-(3,4-dimethoxybenzoyl)-5-methyl-2H-imidazol-2-one meltingat about 257°-259° C. after recrystallization twice from ethanol-water.

1,3-Dihydro-4-(2-furoyl)-5-methyl-2H-imidazol-2-one melting at about214°-216° C. after recrystallization twice from methanol.

1,3-Dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 293°-296° C. (dec).

1,3-Dihydro-5-ethyl-4-(4-methoxybenzyol)-2H-imidazol-2-one melting atabout 132° C. (dec).

1,3-Dihydro-5-methyl-4-(4-pyridinecarbonyl)-2H-imidazol-2-one melting atabout 296° C. (dec).

4-Acetyl-1,3-dihyro-5-methylimidazol-2-one melting at about 314°-316° C.

EXAMPLE 2

The sodium salt of1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one is preparedfrom 7.0 g of1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 100 ml ofmethanol with the addition of 1.6 g of sodium methoxide. A mixture isprepared from 8.0 g of this sodium salt, 120 ml of dimethylsulfoxide,15.2 g of powdered sodium hydroxide, and 19.5 g of methyl iodide. Thismixture is stirred at room temperature for 60 minutes and then pouredinto 800 ml of water. The resulting mixture is then extracted withmethylene chloride and the solvent is evaporated from the extract togive a solid. This is crystallized from ether to give1,3-dihydro-4-(4-methoxybenzoyl)-1,3,5-trimethyl-2H-imidazol-2-onemelting at about 109°-111° C.

EXAMPLE 3

To 2.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-onein 30 ml of dimethyl sulfoxide is added 0.29 g of sodium hydride and1.22 g of methyl iodide. The mixture is stirred at 22° C. for 30minutes, poured in methylene chloride, and washed with water. Themethylene chloride solution is dried and the solvent is evaporated toleave an oil which is triturated with chloroform to give a solid. Thissolid is recrystallized from methanol to give 1,3-dihydro-(1 or 3),5-dimethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about225°-228° C.

EXAMPLE 4

A mixture of 46.4 g of1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one and 200 mlof acetic anhydride is refluxed for 2 hours. The mixture is distilled toremove 100 ml of acetic anhydride and acetic acid; this is replaced byfresh acetic anhydride and refluxing is resumed. After a total of 4hours of reflux, excess acetic anhydride is evaporated under reducedpressure and the resulting residue is crystallized from ethanol to give1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 123°-125° C.

If the above procedure is repeated using acetic anhydride and theappropriate substituted 1,3-dihydro-2H-imidazol-2-one, the followingcompounds are obtained:

4-Benzoyl-1,3-diacetyl-1,3-dihydro-5-methyl-2H-imidazol-2-one melting atabout 120°-122° C.

1,3-Diacetyl-1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 102°-103° C.

1,3-Diacetyl-1,3-dihydro-4-(4-dimethylaminobenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 183°-184° C.

1,3-Dihydro-1,3,4-triacetyl-5-methyl-2H-imidazol-2-one melting at about73°-75° C.

1,3-Diacetyl-1,3-dihydro-4-(3,4-dimethoxybenzoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(4-methylsulfonylbenzoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(2-furoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(2-thiophenecarbonyl)-5-methyl-2H-imidazol-2-one

1,3-Diacetyl-1,3-dihydro-5-methyl-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-5-ethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

EXAMPLE 5

A mixture of 55.5 g (0.176 mole) of1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one,37.4 g (0.210 mole) of N-bromosuccinimide and about 100 mg of benzoylperoxide in 500 ml of carbon tetrachloride is stirred at refluxtemperature for 4 hours. The mixture is then cooled and filtered toremove the succinimide which formed. The solvent is evaporated from thefiltrate and the resulting residue is crystallized from a mixture of 300ml of ethyl acetate and 300 ml of hexane to give5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onemelting at about 135°-136° C.

If the above procedure is repeated using N-bromosuccinimide and theappropriate substituted 1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one, thefollowing compounds are obtained:

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-onemelting at about 113°-120° C.

5-(Bromomethyl)-1,3-dihydro-1,3,4-triacetyl-2H-imidazol-2-one melting atabout 88°-90° C.

4-Benzoyl-5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(3,4-dimethoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methylsulfonylbenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-dimethylaminobenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(2-furoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(2-thiophenecarbonyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

5-(1-Bromoethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-1,3-dimethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-1 or3)-methyl-2H-imidazol-2-one.

EXAMPLE 6

A mixture of 50 g of5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onein 75 ml of 30% hydrobromic acid in acetic acid and 150 ml of aceticacid is heated to 80° C. on a steam bath and allowed to stand for 2hours. The mixture is then evaporated to dryness under reduced pressureand the residue is crystallized from acetic acid and then dried in vacuoat 80° C. over potassium hydroxide. This gives5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onemelting at about 205°-207° C. with decomposition.

If the above procedure is repeated using the appropriate5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one, thefollowing products are obtained:

5-(Bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-onemelting at greater than 300° C. with decomposition.

4-Benzoyl-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(3,4-dimethoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-methylsulfonylbenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-dimethylaminobenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(2-furoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(2-thiophenecarbonyl)-2H-imidazol-2-one.

4-Acetyl-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

5-(1-Bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

EXAMPLE 7

A mixture of 4.7 g (15 mmole) of5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one, 2.5g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassiumcarbonate and 75 ml of ethanol is stirred at 25° C. for 16 hours. Water(100 ml) is added and a precipitate forms. This is separated byfiltration and washed with water. It is then suspended in 2-propanol and1 equivalent of hydrogen chloride in 2-propanol is added. The resultingsolid is separated by filtration and recrystallized from 2-propanolcontaining a little water to give1,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride melting at about 230° C. with decomposition.

EXAMPLE 8

If the procedure of Example 7 is repeated using 4-phenylpiperidine andthe appropriate4-substituted-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one, thefollowing compounds are obtained:

4-Benzoyl-1,3-dihydro-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-4-(3,4-dimethoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-4-(3,4-methylenedioxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-4-[4-(methylsulfonyl)benzoyl]-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-4-(4-methoxybenzoyl)-1,3-dimethyl-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-4-(2-furoyl)-5-[(4-phenyl-1-piperidinyl)-methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-5-[(4-phenyl-1-piperidinyl)methyl]-4-(2-thiophenecarbonyl)-2H-imidazol-2-onehydrochloride.

4-Acetyl-1,3-dihydro-5-[(4-phenyl-1-piperidinyl)-methyl]-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-5-[(4-phenyl-1-piperidinyl)methyl]-4-(4-pyridinecarbonyl)-2H-imidazol-2-onehydrochloride.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-[1-(4-phenyl-1-piperidinyl)ethyl]-2H-imidazol-2-onehydrochloride.

EXAMPLE 9

A mixture of 4.3 g (14.2 mmole) of5-(bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-one, 3.0 g(14.2 mmole) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2mmole) of potassium carbonate and 75 ml of ethanol is stirred underargon for 16 hours at 25° C. Water (100 ml) is added and the precipitatewhich forms is collected and washed with water. It is then suspended in2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added.The resulting solid is separated and recrystallized twice from a mixtureof 2-propanol and water to give4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-onehydrochloride melting at about 235°-236° C. with decomposition.

EXAMPLE 10

If the procedure of Example 9 is repeated using5-(bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-one andthe appropriate 4-substituted piperidine, the following compounds areobtained:

5-(4-Fluorobenzoyl)-4-[(4-phenyl-1,2,3,6-tetrahydro-1-pyridinyl)methyl]-1,3-dihydro-2H-imidazol-2-onehydrochloride.

5-(4-Fluorobenzoyl)-4-[[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridinyl]methyl]-1,3-dihydro-2H-imidazol-2-onehydrochloride.

4-[(4-Acetyl-4-phenyl-1-piperidinyl)methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-onehydrochloride.

4-[[(4-Cyano-4-phenyl-1-piperidinyl)methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-onehydrochloride.

4-[(4-Ethoxycarbonyl-4-phenyl-1-piperidinyl)methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-onehydrochloride.

4-[[4-Ethoxycarbonyl-4-(4-chlorophenyl)-1-piperidinyl]methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-onehydrochloride.

5-(4-Fluorobenzoyl)-4-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]methyl]-1,3-dihydro-2H-imidazol-2-onehydrochloride.

5-(4-Fluorobenzoyl)-4-[[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]methyl]-1,3-dihydro-2H-imidazol-2-onehydrochloride.

EXAMPLE 11

1,3-Dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-onehydrochloride is converted to the free base by standard procedures andthen treated with a large excess of refluxing acetic anhydride for 4hours. Excess acetic anhydride is evaporated under reduced pressure andthe resultant residue is recrystallized twice from a mixture of ethylacetate and ethanol to give1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-one.

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R ishydrogen, lower alkyl of 1-4 C, lower alkanoyl of 2-4 C, or benzoyl; R¹is lower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl,methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl,dimethoxyphenyl, 3,4-methylenedioxyphenol, 2-furyl, 2-thienyl orpyridyl; R² is hydrogen or lower alkyl of 1-4 C; X is hydrogen halogen,methyl, methoxy or trifluoromethyl; Y is hydrogen, hydroxy, cyano,acetyl or (C₁₋₄ lower alkoxy)carbonyl; Y¹ is hydrogen or Y and Y¹together form a double bond; and the pharmaceutically acceptable acidaddition salts.
 2. A compound according to claim 1 which has theformula: ##STR7## wherein R¹ is lower alkyl of 1-4 C, phenyl,halophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl,dimethylaminophenyl, dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furyl,2-thienyl or pyridyl; X is hydrogen, halogen, methyl, methoxy andtrifluoromethyl; Y is hydrogen, hydroxy, cyano, acetyl or (C₁₋₄ loweralkoxy)carbonyl; Y¹ is hydrogen or Y and Y¹ together form a double bond.3. A compound according to claim 1 which has the formula: ##STR8##wherein R¹ is lower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl,methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl,dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furyl, 2-thienyl orpyridyl.
 4. A compound according to claim 1 which is1,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-one.5. A compound according to claim 1 which is4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-one.